Oridonin Sensitizes Cisplatin-Induced Apoptosis via AMPK/Akt/mTOR-Dependent Autophagosome Accumulation in A549 Cells
Identifieur interne : 000563 ( Pmc/Curation ); précédent : 000562; suivant : 000564Oridonin Sensitizes Cisplatin-Induced Apoptosis via AMPK/Akt/mTOR-Dependent Autophagosome Accumulation in A549 Cells
Auteurs : Huahong Yang [République populaire de Chine] ; Yun Gao [République populaire de Chine] ; Xiaoye Fan [République populaire de Chine] ; Xingkai Liu [République populaire de Chine] ; Liping Peng [République populaire de Chine] ; Xinxin Ci [République populaire de Chine]Source :
- Frontiers in Oncology [ 2234-943X ] ; 2019.
Abstract
AMPK-mediated autophagy and Akt/mTOR pathways play important roles in current cancer treatments. Oridonin (Ori), an ent-kaurane diterpenoid isolated from Isodon rubescens, exerts extensive anti-tumor potential and controversial effects on autophagy. In this study, we investigated the effect of Ori on the autophagy, apoptosis, and AMPK/Akt/mTOR pathways and determined whether Ori was related to the increased cisplatin sensitivity observed in A549 cells. First, we found that Ori suppressed Akt/mTOR, Bcl2 and autophagy flux with enhanced levels of Atg3, P62, and LC3II, which was also shown as the accumulation of autophagosomes. AMPK and pro-apoptotic proteins (caspase3, Bax, and PARP) were activated in Ori-treated cells. With the pretreatment of compound c (AMPK inhibitor), the activation of autophagosomes, apoptosis and the inhibition of Akt/mTOR pathways induced by Ori were all reversed. The Ori-activated apoptosis-related markers mentioned previously and the cell-killing effect were restrained by 3-MA (inhibitor of autophagosomes) treatment. Therefore, we hypothesized that the Ori-induced pro-apoptotic effect was mediated by AMPK/Akt/mTOR-dependent accumulation of impaired autophagosomes. Furthermore, Ori could increase the sensitivity of cisplatin through its increased cell-killing, autophagy-suppressing and apoptosis-inducing activities. In addition to sensitizing cisplatin, Ori also alleviated cisplatin-induced acute renal injury
Url:
DOI: 10.3389/fonc.2019.00769
PubMed: 31475112
PubMed Central: 6702493
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Oridonin Sensitizes Cisplatin-Induced Apoptosis via AMPK/Akt/mTOR-Dependent Autophagosome Accumulation in A549 Cells</title><author><name sortKey="Yang, Huahong" sort="Yang, Huahong" uniqKey="Yang H" first="Huahong" last="Yang">Huahong Yang</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Respiratory Medicine, The First Hospital of Jilin University</institution>,<addr-line>Changchun</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Gao, Yun" sort="Gao, Yun" uniqKey="Gao Y" first="Yun" last="Gao">Yun Gao</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Respiratory Medicine, The First Hospital of Jilin University</institution>,<addr-line>Changchun</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Fan, Xiaoye" sort="Fan, Xiaoye" uniqKey="Fan X" first="Xiaoye" last="Fan">Xiaoye Fan</name><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Institute of Translational Medicine, The First Hospital of Jilin University</institution>,<addr-line>Changchun</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Liu, Xingkai" sort="Liu, Xingkai" uniqKey="Liu X" first="Xingkai" last="Liu">Xingkai Liu</name><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Department of Hepatopancreatobiliary Surgery, The First Hospital of Jilin University</institution>,<addr-line>Changchun</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Peng, Liping" sort="Peng, Liping" uniqKey="Peng L" first="Liping" last="Peng">Liping Peng</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Respiratory Medicine, The First Hospital of Jilin University</institution>,<addr-line>Changchun</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Ci, Xinxin" sort="Ci, Xinxin" uniqKey="Ci X" first="Xinxin" last="Ci">Xinxin Ci</name><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Institute of Translational Medicine, The First Hospital of Jilin University</institution>,<addr-line>Changchun</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31475112</idno><idno type="pmc">6702493</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702493</idno><idno type="RBID">PMC:6702493</idno><idno type="doi">10.3389/fonc.2019.00769</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000563</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000563</idno><idno type="wicri:Area/Pmc/Curation">000563</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000563</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Oridonin Sensitizes Cisplatin-Induced Apoptosis via AMPK/Akt/mTOR-Dependent Autophagosome Accumulation in A549 Cells</title><author><name sortKey="Yang, Huahong" sort="Yang, Huahong" uniqKey="Yang H" first="Huahong" last="Yang">Huahong Yang</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Respiratory Medicine, The First Hospital of Jilin University</institution>,<addr-line>Changchun</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Gao, Yun" sort="Gao, Yun" uniqKey="Gao Y" first="Yun" last="Gao">Yun Gao</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Respiratory Medicine, The First Hospital of Jilin University</institution>,<addr-line>Changchun</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Fan, Xiaoye" sort="Fan, Xiaoye" uniqKey="Fan X" first="Xiaoye" last="Fan">Xiaoye Fan</name><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Institute of Translational Medicine, The First Hospital of Jilin University</institution>,<addr-line>Changchun</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Liu, Xingkai" sort="Liu, Xingkai" uniqKey="Liu X" first="Xingkai" last="Liu">Xingkai Liu</name><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Department of Hepatopancreatobiliary Surgery, The First Hospital of Jilin University</institution>,<addr-line>Changchun</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Peng, Liping" sort="Peng, Liping" uniqKey="Peng L" first="Liping" last="Peng">Liping Peng</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Respiratory Medicine, The First Hospital of Jilin University</institution>,<addr-line>Changchun</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Ci, Xinxin" sort="Ci, Xinxin" uniqKey="Ci X" first="Xinxin" last="Ci">Xinxin Ci</name><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Institute of Translational Medicine, The First Hospital of Jilin University</institution>,<addr-line>Changchun</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">Frontiers in Oncology</title><idno type="eISSN">2234-943X</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>AMPK-mediated autophagy and Akt/mTOR pathways play important roles in current cancer treatments. Oridonin (Ori), an ent-kaurane diterpenoid isolated from Isodon rubescens, exerts extensive anti-tumor potential and controversial effects on autophagy. In this study, we investigated the effect of Ori on the autophagy, apoptosis, and AMPK/Akt/mTOR pathways and determined whether Ori was related to the increased cisplatin sensitivity observed in A549 cells. First, we found that Ori suppressed Akt/mTOR, Bcl2 and autophagy flux with enhanced levels of Atg3, P62, and LC3II, which was also shown as the accumulation of autophagosomes. AMPK and pro-apoptotic proteins (caspase3, Bax, and PARP) were activated in Ori-treated cells. With the pretreatment of compound c (AMPK inhibitor), the activation of autophagosomes, apoptosis and the inhibition of Akt/mTOR pathways induced by Ori were all reversed. The Ori-activated apoptosis-related markers mentioned previously and the cell-killing effect were restrained by 3-MA (inhibitor of autophagosomes) treatment. Therefore, we hypothesized that the Ori-induced pro-apoptotic effect was mediated by AMPK/Akt/mTOR-dependent accumulation of impaired autophagosomes. Furthermore, Ori could increase the sensitivity of cisplatin through its increased cell-killing, autophagy-suppressing and apoptosis-inducing activities. In addition to sensitizing cisplatin, Ori also alleviated cisplatin-induced acute renal injury <italic>in vivo</italic>, manifested as depleted BUN, CRE, kidney index, and weight loss compared to the cisplatin group. In summary, apart from its protective effect on cisplatin-induced nephrotoxicity, Ori enhanced cisplatin sensitivity via its pro-apoptotic activity mediated by AMPK/Akt/mTOR-dependent autophagosome activation, which may be a potential therapeutic target for non-small cell lung cancer.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Hirsch, Fr" uniqKey="Hirsch F">FR Hirsch</name></author><author><name sortKey="Suda, K" uniqKey="Suda K">K Suda</name></author><author><name sortKey="Wiens, J" uniqKey="Wiens J">J Wiens</name></author><author><name sortKey="Bunn, Pa" uniqKey="Bunn P">PA Bunn</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Neal, Rd" uniqKey="Neal R">RD Neal</name></author><author><name sortKey="Hamilton, W" uniqKey="Hamilton W">W Hamilton</name></author><author><name sortKey="Rogers, Tk" uniqKey="Rogers T">TK 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Front Oncol</journal-id><journal-id journal-id-type="iso-abbrev">Front Oncol</journal-id><journal-id journal-id-type="publisher-id">Front. Oncol.</journal-id><journal-title-group><journal-title>Frontiers in Oncology</journal-title></journal-title-group><issn pub-type="epub">2234-943X</issn><publisher><publisher-name>Frontiers Media S.A.</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31475112</article-id><article-id pub-id-type="pmc">6702493</article-id><article-id pub-id-type="doi">10.3389/fonc.2019.00769</article-id><article-categories><subj-group subj-group-type="heading"><subject>Oncology</subject><subj-group><subject>Original Research</subject></subj-group></subj-group></article-categories><title-group><article-title>Oridonin Sensitizes Cisplatin-Induced Apoptosis via AMPK/Akt/mTOR-Dependent Autophagosome Accumulation in A549 Cells</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Yang</surname><given-names>Huahong</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Gao</surname><given-names>Yun</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Fan</surname><given-names>Xiaoye</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Liu</surname><given-names>Xingkai</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Peng</surname><given-names>Liping</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="corresp" rid="c001"><sup>*</sup></xref></contrib><contrib contrib-type="author"><name><surname>Ci</surname><given-names>Xinxin</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref><xref ref-type="corresp" rid="c002"><sup>*</sup></xref><uri xlink:type="simple" xlink:href="http://loop.frontiersin.org/people/427513/overview"></uri></contrib></contrib-group><aff id="aff1"><sup>1</sup><institution>Department of Respiratory Medicine, The First Hospital of Jilin University</institution>,<addr-line>Changchun</addr-line>,<country>China</country></aff><aff id="aff2"><sup>2</sup><institution>Institute of Translational Medicine, The First Hospital of Jilin University</institution>,<addr-line>Changchun</addr-line>,<country>China</country></aff><aff id="aff3"><sup>3</sup><institution>Department of Hepatopancreatobiliary Surgery, The First Hospital of Jilin University</institution>,<addr-line>Changchun</addr-line>,<country>China</country></aff><author-notes><fn fn-type="edited-by"><p>Edited by: Simona Rapposelli, University of Pisa, Italy</p></fn><fn fn-type="edited-by"><p>Reviewed by: Daniela Cesselli, University of Udine, Italy; Grazia Chiellini, University of Pisa, Italy</p></fn><corresp id="c001">*Correspondence: Liping Peng <email>plp640317@163.com</email></corresp><corresp id="c002">Xinxin Ci <email>cixinxin@jlu.edu.cn</email></corresp><fn fn-type="other" id="fn001"><p>This article was submitted to Pharmacology of Anti-Cancer Drugs, a section of the journal Frontiers in Oncology</p></fn></author-notes><pub-date pub-type="epub"><day>14</day><month>8</month><year>2019</year></pub-date><pub-date pub-type="collection"><year>2019</year></pub-date><volume>9</volume><elocation-id>769</elocation-id><history><date date-type="received"><day>10</day><month>5</month><year>2019</year></date><date date-type="accepted"><day>30</day><month>7</month><year>2019</year></date></history><permissions><copyright-statement>Copyright © 2019 Yang, Gao, Fan, Liu, Peng and Ci.</copyright-statement><copyright-year>2019</copyright-year><copyright-holder>Yang, Gao, Fan, Liu, Peng and Ci</copyright-holder><license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</license-p></license></permissions><abstract><p>AMPK-mediated autophagy and Akt/mTOR pathways play important roles in current cancer treatments. Oridonin (Ori), an ent-kaurane diterpenoid isolated from Isodon rubescens, exerts extensive anti-tumor potential and controversial effects on autophagy. In this study, we investigated the effect of Ori on the autophagy, apoptosis, and AMPK/Akt/mTOR pathways and determined whether Ori was related to the increased cisplatin sensitivity observed in A549 cells. First, we found that Ori suppressed Akt/mTOR, Bcl2 and autophagy flux with enhanced levels of Atg3, P62, and LC3II, which was also shown as the accumulation of autophagosomes. AMPK and pro-apoptotic proteins (caspase3, Bax, and PARP) were activated in Ori-treated cells. With the pretreatment of compound c (AMPK inhibitor), the activation of autophagosomes, apoptosis and the inhibition of Akt/mTOR pathways induced by Ori were all reversed. The Ori-activated apoptosis-related markers mentioned previously and the cell-killing effect were restrained by 3-MA (inhibitor of autophagosomes) treatment. Therefore, we hypothesized that the Ori-induced pro-apoptotic effect was mediated by AMPK/Akt/mTOR-dependent accumulation of impaired autophagosomes. Furthermore, Ori could increase the sensitivity of cisplatin through its increased cell-killing, autophagy-suppressing and apoptosis-inducing activities. In addition to sensitizing cisplatin, Ori also alleviated cisplatin-induced acute renal injury <italic>in vivo</italic>, manifested as depleted BUN, CRE, kidney index, and weight loss compared to the cisplatin group. In summary, apart from its protective effect on cisplatin-induced nephrotoxicity, Ori enhanced cisplatin sensitivity via its pro-apoptotic activity mediated by AMPK/Akt/mTOR-dependent autophagosome activation, which may be a potential therapeutic target for non-small cell lung cancer.</p></abstract><kwd-group><kwd>oridonin</kwd><kwd>non-small cell lung cancer</kwd><kwd>cisplatin sensitivity</kwd><kwd>autophagy</kwd><kwd>apoptosis</kwd><kwd>AMPK/Akt/mTOR</kwd></kwd-group><funding-group><award-group><funding-source id="cn001">National Natural Science Foundation of China<named-content content-type="fundref-id">10.13039/501100001809</named-content></funding-source><award-id rid="cn001">81870030</award-id></award-group><award-group><funding-source id="cn002">China Postdoctoral Science Foundation<named-content content-type="fundref-id">10.13039/501100002858</named-content></funding-source><award-id rid="cn002">2018T110257</award-id></award-group></funding-group><counts><fig-count count="7"></fig-count><table-count count="0"></table-count><equation-count count="0"></equation-count><ref-count count="43"></ref-count><page-count count="13"></page-count><word-count count="6242"></word-count></counts></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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